title: Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo.
abstract: Highly active antiretroviral therapy (HAART) decreases plasma viremia below the limits of detection in the majority of HIV-infected individuals, thus serving to slow disease progression. However, HAART targets only actively replicating virus and is unable to eliminate latently infected, resting CD4(+) T cells. Such infected cells are potentially capable of reinitiating virus replication upon cessation of HAART, thus leading to viral rebound. Agents that would eliminate these reservoirs, when used in combination with HAART, could thus provide a strategy for the eradication of HIV. Prostratin is a preclinical candidate that induces HIV expression from latently infected CD4(+) T cells, potentially leading to their elimination through a virus-induced cytopathic effect or host anti-HIV immunity. Here, we report the synthesis of a series of designed prostratin analogs and report in vitro and ex vivo studies of their activity relevant to induction of HIV expression. Members of this series are up to 100-fold more potent than the preclinical lead (prostratin) in binding to cell-free PKC, and in inducing HIV expression in a latently infected cell line and prostratin-like modulation of cell surface receptor expression in primary cells from HIV-negative donors. Significantly, selected members were also tested for HIV induction in resting CD4(+) T cells isolated from infected individuals receiving HAART and were found to exhibit potent induction activity. These more potent agents and by extension related tunable analogs now accessible through the studies described herein should facilitate research and preclinical advancement of this strategy for HIV/AIDS eradication.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Beans
authors.forename: Dennis
authors.initials: D
authors.lastname: Fournogerakis
authors.forename: Carolyn
authors.initials: C
authors.lastname: Gauntlett
authors.forename: Lars V
authors.initials: LV
authors.lastname: Heumann
authors.forename: Rainer
authors.initials: R
authors.lastname: Kramer
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Marsden
authors.forename: Danielle
authors.initials: D
authors.lastname: Murray
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chun
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Zack
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wender
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010703:Phorbol Esters / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D014775:Virus Activation / Q000187:drug effects* / Q000502:physiology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D010703:Phorbol Esters; D011493:Protein Kinase C; D000099192:CD69 Antigens; C070999:prostratin
keywords: HIV latency; NF-κB; PKC-δ; bryostatin